UB researchers use antibiotics combination to kill the first strain of highly resistant E. coli in the United States

Fewer than two dozen cases of E. coli carrying mcr-1 have been reported in the U.S., however, the bacteria’s immunity to available antibiotics has left the medical community vulnerable to a massive outbreak of infections. Photo: Douglas Levere

“We had to work quickly and think outside of the box, beyond traditional antibiotic combinations.”

Brian Tsuji, PharmD, principal investigator and associate professor in the School of Pharmacy and Pharmaceutical Sciences

BUFFALO, N.Y. – The golden age of antibiotics may be
drawing to a close.

The recent discovery of E. coli carrying mcr-1 and ndm-5 —
genes that make the bacterium immune to last-resort antibiotics
— has left clinicians without an effective means of treatment
for the superbug.

But in a new study, University at Buffalo researchers have
assembled a team of three antibiotics that, together, are capable
of eradicating the deadly bacterium. The groundbreaking research
was recently published in mBio, a journal for the American Society
of Microbiology.

The researchers found that a novel combination of aztreonam,
amikacin and polymyxin B — a last-resort antibiotic —
was able to kill E. coli carrying mcr-1 and ndm-5 genes within 24
hours while also preventing regrowth. Traditional combinations of
these antibiotics were unable to kill the E. coli and resulted in
rapid resistance.

“The threat of gram-negative bacteria, including E. coli
carrying mcr-1, is worrisome,” says Zackery Bulman, PharmD,
first author on the study, a graduate and former postdoctoral
fellow at the UB School of Pharmacy and Pharmaceutical Sciences who
is now an assistant professor at the University of Illinois at
Chicago College of Pharmacy.

“We believe that the appearance of mcr-1 and ndm-5 in
patients may be a harbinger for what is to come. The golden era of
antibiotics isn’t over yet, but we wanted to help clinicians
prepare therapeutically for the occurrence of these
strains.”

Brian Tsuji, PharmD, principal investigator and associate
professor in the School of Pharmacy and Pharmaceutical Sciences,
continued: “That is why the mcr-1 and ndm-5 strains represent
an urgent threat, because of the high-degree of resistance combined
with the potential for rapid spread in the community setting. We
had to work quickly and think outside of the box, beyond
traditional antibiotic combinations.”

“This is the first study to propose therapeutic solutions
with three drugs against superbugs harboring mcr-1 and ndm-5. The
results will help prepare clinicians for future occurrences of
these pathogens.”

Fewer than two dozen cases of E. coli carrying mcr-1 have been
reported in the U.S. However, with additional cases reported
worldwide, the bacteria’s immunity to available antibiotics
has left the medical community vulnerable to a massive outbreak of
infections.

The rapid increase in antibiotic-resistant bacteria has
resurrected the importance of polymyxins, a class of antibiotics
that are effective but employed as a last resort because of the
damage they can cause to the kidneys.

To avoid prescribing high dosages of polymyxins and to make up
for the antibiotic’s weaknesses, the researchers decided to
turn to new dosing strategies and multiple antibiotic
combinations.

After conducting studies on dozens of combinations of more than
15 antibiotics paired with polymyxin B, the researchers discovered
two effective treatments. Combinations of polymyxin B with either
aztreonam or amikacin resulted in undetectable bacterial counts
after 24 hours.

The E. coli, however, was able to regrow to initial levels after
96 hours and a subpopulation of amikacin-resistant strains arose
after 10 days when exposed to the combination of polymyxin B and
amikacin. Polymyxin B and aztreonam pushed the E. coli into a
persistent but nonreplicating state. Only the triple combination
eliminated the E. coli strain and prevented regrowth.

“We knew that polymyxins alone couldn’t work. Only
the three drugs combined were able to work synergistically to
suppress and kill the bacteria,” says Bulman. “We
overcame the bacteria by pushing it as far as possible with an
agent that it was resistant to while simultaneously administering
two other antibiotics.”

The promising finding may provide a viable treatment against
mcr-1 and ndm-5 strains.

The research was funded through a $4.4 million National
Institutes of Health (NIH) grant awarded to Tsuji to develop new
dosing regimens for polymyxins.